通过基于结构的设计实现蛋白激酶B的6-苯基嘌呤抑制剂的快速进化。
Rapid evolution of 6-phenylpurine inhibitors of protein kinase B through structure-based design.
作者信息
Donald Alastair, McHardy Tatiana, Rowlands Martin G, Hunter Lisa-Jane K, Davies Thomas G, Berdini Valerio, Boyle Robert G, Aherne G Wynne, Garrett Michelle D, Collins Ian
出版信息
J Med Chem. 2007 May 17;50(10):2289-92. doi: 10.1021/jm0700924. Epub 2007 Apr 24.
6-phenylpurines were identified as novel, ATP-competitive inhibitors of protein kinase B (PKB/Akt) from a fragment-based screen and were rapidly progressed to potent compounds using iterative protein-ligand crystallography with a PKA-PKB chimeric protein. An elaborated lead compound showed cell growth inhibition and effects on cellular signaling pathways characteristic of PKB inhibition.
通过基于片段的筛选，6-苯基嘌呤被鉴定为蛋白激酶B（PKB/Akt）的新型ATP竞争性抑制剂，并利用PKA-PKB嵌合蛋白通过迭代蛋白质-配体晶体学迅速发展为强效化合物。一种经过精心设计的先导化合物显示出细胞生长抑制作用以及对PKB抑制所特有的细胞信号通路的影响。
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